Gut Brain Axis
Describe the brain in the gut, what is it called?
The gut is a tube and inside the tube there are groups of neurons that line the gut and are important for ingestion, digestion, and excretion and host defense.
It is called the enteric nervous system (ENS).
The brain in the gut and the brain in the head are connected through ____.
Autonomic nerves
The enteric nervous system connects to ___ and ___ pathways.
Vagal and pelvic pathways
____ pathways connect to enteric nervous system and innverate structures directly.
Sympathetic
____ innervations go to the enteric nervous system first and then enteric nervous system intergrates that neural activity from the brain and the spinal cord
Autonomic
____ nerves go from the gut back to the spinal cord through primary ____ pathways and vagal pathways.
Sensory, afferent
The enteric nervous system is a distinct division of the _____ system.
Autonomic
What does the enteric nervous system consist of? What does it do?
Consists of neurons and glial
Has as many neurons as the spinal cord
Contains multiple neurotransmitters and messenger systems like the brain
Independently controls gut function (this is what really distinguishes it)
What is the law of the intestine (peristaltic reflex)? Why does this distinguish the gut from other organs?
When you put stimulus in the gut, contraction occurs orally and relaxation occurs anally and creates propulsion down the gut.
If you cut nerves to the gut, it will still push stimulus through it. If you cut nerves to the heart (or other organs), it will stop working. When you paralyze the nerves in the ENS, it can't move the stimulus along but there are still contractions. This proves the ENS is what controls the movement along the gut, and can work by itself
When a stimulus activates the gut it activates a group of cells within the wall of the gut called ____
Enteroendocrine cells
Explain the process when enteroendocrine cells are activated.
They release chemicals to activate sensory nerves that lie in the two plexuses, which then activate interneurons. It activates motor neurons in the oral direction, which are excitatory, and give rise to contractions. The activate inhibitory neurons in the anal direction which give rise to relaxation.
This contraction and relaxation set up the pressure gradient.
Reflexes are modified by glial cells, they play an important role in the ENS.
Intrinsic reflex circuits that control motility involved ___, ___, and ___ signalling.
Enteroendocrine, neural, and glial signaling
Name the inhibitory, excitatory, and co-transmitters of the enteric motility reflex circuitry.
Inhibitory: Nitric Oxide
Excitatory: Acetylcholine
Co-transmitters: substance P and other peptides
Ascending neurons are going toward the ____. Descending neurons are going toward the____
Oral end, anal end
Describe the human microbiome.
Community of 100+ trillion microrganisms (viruses, bacteria, protozooans, archea, and fungi
Mutualistic (they benefit the host and the microbiome)
Its metabolic output is so vast and so important it is considerd its own organ
The gut has the largest proportion of microbes than any other site in the body
True or false: The gut microbiome comes from your father.
Explain how the gut microbiome develops as a person ages.
False. The gut microbiome comes from your mother by way of birth (vaginally, c-section, etc)
Babies are born 'sterile.' They gets 'bugs' and takes about 5-10 years to become stable. It is influenced during puberty, becomes fully developed in late teens or early 20s. Can be affected by early life factors (antibiotics, diet, genetics)
List the main metabolic roles of the intestinal microbiota.
Metabolic role, role in inhibition of pathogenic bacteria, and developmental/defensive role
Explain the metabolic role of intestinal microbiota.
Digests food that can't be digested
Promote digestion and energy utilization: fermentation of non-digestible food
Facilitate absorption of dietary minerals
-Synthesis of metabolites (short chain fatty acids, vitamin K, B12, biotin etc)
Microbiome possess the enzymatic tools to degrade and synthesize a large variety of compounds
Explain the role of intestinal microbiota in inhibition of pathogenic bacteria.
Protects against microbes, toxins, etc.
Explain the developmental/defensive role of intestinal microbiota.
Development of the intestinal mucosa and immune system
Microbiome stimulate production of regulatory T cells
List the microbial signals that impact gut and CNS (patho) physiology.
Short chain fatty acids (acetate, butyrate, etc)
Microbe-associated molecular patterns (TLR ligands, NLR ligands)
Ligand-activated transcription factor receptor ligands (tryptophan metabolites)
Quorum sensing molecules (acyl homoserine lactones) (microbiota talk to eachother through quorom sensing molecules)
List and describe the three pathways of how enteric microbiota enter the brain.
Humoral pathway: Cytokines from activate monocytes and macrophages enter the brain through CVOs (leaky areas of the blood brain barrier)
Neural pathway: Cytokines from activated monocytes and macrophages stimulate nerve fibres in the vagus nerve, which then relays information to the brain (direct stimulation between the gut and the brain)
Cellular pathway: Cytokines stimulate microglia which produce MCP-1, which recruits monocytes into the brain.
Luminal stimuli are sensed by ___ nerves
Sensory
What are transducers and why are they important?
Nerves don't penetrate beyond the epithelium, so nerves in the gut going to the brain need a transducer to know whats doing on in the lumen. The transducers are the enteroendocrine cells (specialized epithelial cells)
Where are enteroendocrine cells that transduce luminal stimuli located?
Located throughout the length of the GI tract. Different types line different areas of the gut and signal using different molecules (peptides and biological amine (5-HT))
Enteroendocrine cells and immune cells also transduce ____ signals.
Microbial signals.
Bacteria talk to enteroendocrine cells and E cells talk to the immune system
_____ is an important activator of gastrointestinal afferents.
Serotonin (5-HT)
Talk about serotonin in the gut.
The majority of the body's serotonin is in the bowel, and most 5-HT in the bowl is synthesized by enterchromaffin (EC) cells.
5-HT released from EC cells can initiate reflex responses, such as intestinal secretion and peristalsis, and when released in large amounts it can cause nausea and vomiting
5-HT actions are terminated by reuptake involving the same serotonin-selective transporter (SERT) that is found in the CNS
Levels of 5-HT and colonic motility are regulated by ____
Bacteria/ gut microbes.
If you don't have bacteria you will have less 5-HT and slower function.
List the five pathways that interact in the gut wall.
Neural (enteric and autonomic)
Glial
Enteroendocrine
Microbial
Immunological pathways
Enteroendocrine cells transduce luminal stimuli and ___ (4 things)
Mechanical
Chemical
Toxins
Radiation
Piezo channels confer _____ to a population of enteroendocrine cells.
Mechanosensitivity.
The gut has a sense of touch using the same mechanosensitive channels that are used for sense of touch in the skin.
What are neuropods? What do they do?
Neuropods cells are in the intestinal epithelium and contain both large dense-core neuropeptide vesicles and small neurotransmitter vesicles. They have the capacity to receive afferent signalling from lumin from enteroendocrine cells to nerves, and also efferent signaling.
Enteroendocrine cells can transduce luminal stimuli using which neurotransmitter?
Glutamate
Afferent nerves involve fast neurotransmission. Enteroendocrine cells can release glutamate and signal to nerves in a fast neurotransmitter.
Sympathetic nerve-enteroendocrine L cell communication modulates ___, ___, and ___
GLP-1 release (GLP-1 regulates glucose uptake and brain blood flow, regulating glucose utilization in the liver and brain)
Brain glucose utilization
Cognitive function
This is an example of gut-brain communication involving autonomic nerves regulating gut peptide release to influence learning and memory
Which protein is present in enteroendocrine cells and enteric nerves?
a-synuclein
Enteroendocrine cells express a-synuclein, misfolding of this can lead to neurodegenerative diseases. A-synuclein is able to transmit to the nerves that underly it, then goes through the vagus to the brain stem (why PD patients have brain stem lesions before motor lesions in the substantia nigra and basal ganglia
Describe the intestinal transit of germ free rats.
Germ free rats have altered small intestinal transit. Germ free anything has slower motility.
Describe enteric primary afferent neurons.
They are mostly likely to be impacted by the gut microbiome
They are a specific type of enteric neuron.
Resting membrane potential is around -65mV
Rapid accomodation
Prolonged afterhyperpolarization
Spontaneous activity is rare
Slow excitatory synaptic potentials are common, but fast synaptic potentials are rare
What alters the firing properties of enteric primary afferent neurons?
Microbial products and probiotic bacteria
Electrophysiological recordings of enteric primary afferent neurons showed short chain fatty acids specifically stimulate those nerves and microbial products are involved in activating those nerves.
Specifically, what type of microbiota alter the firing properties of enteric primary afferent neurons?
Enteric microbiota
Action potential threshold activation is higher in germ free mice and they fire less action potentials (they are less excitable)
What does antibiotic treatment that depletes enteric bacteria do?
It alters fluid balance and intestinal transit (changes water balance in the gut)
The gut will completely recover after stopping antibiotics.
If there is enough antibiotics to kill everything in the gut, you will lose enteric neurons.
What do enteric microbiota mediate (two parts)?
1. They mediate glial homeostasis in the mucosa of the GI tract.
Neurons and glial are regulated by the prescence of microbiota
In germ free mice there are less glial cells.
2. They mediate bacterial signaling to innate immune cells (type 3 innate lymphoid cells) to provide IL-22 via neurotrophic factor signaling.
Aka. Important for immune function because they regulate the immune system
What regulates the anatomy and function in germ free mice?
5-HT4 receptors
Serotonin is important in enteric neuronal homeostasis
What happens when you transplant fecal microbiota from patients with IBS to mice?
1. The microbiota alters gut function in germ free mice.
Mice got the same IBS symptom as the human donor.
2. The microbiota alters behaviour in germ free mice.
Mice got anxiogenic effects from human donors with anxiety (due to change in BDNF levels)
What happens if you transfer microbiota from a mouse who exercises to a germ free mouse that doesn't exercise?
You will stimulate the mouse's ability to run on a wheel. If you deplete the microbiota, you deplete their motivation to run.
This is due to striatal dopamine mediated by gut sensory nerves that are regulated by endocannabinoids.